Our previous studies demonstrate that diabetic cardiac diastolic dysfunction (DD), and heart failure with preserved ejection fraction (HFpEF) is mediated by hypomagnesemia (HypoMg) and cardiac macrophage (Mφ) activation. Transient receptor potential cation channel subfamily M 7 (TRPM7), a chanzyme with channel (mainly Mg 2+ /Ca2+ transport) and kinase function, is increased in diabetic and HypoMg hearts. TRPM7 kinase inhibition prevents diabetes- and HypoMg-mediated DD. Here, we investigated TRPM7’s roles on promoting HFpEF in cardiomyocytes (CMs) and Mφs. Wild type (WT) C57BL/6J, transgenic TRPM7 K1646R (no kinase function), and Mφ-specific FABP4 knockout (MφFKO, no Mφ expression of IL-1β/IL-6/TNF-α) mice were fed with normal (control, 2 g/kg Mg 2+ ) or low-Mg (HypoMg, 15–30 mg/kg Mg 2+ , 6 weeks) diet. Human CM cells RL-14 and mouse Mφ cells Raw264.7 were treated with normal (0.81 mM Mg 2+ ) or low-Mg medium (0.04 mM Mg 2+ ) for 48 h. Cardiac Mφs phenotype, protein expression and IL-1β secretion were tested. WT-HypoMg mice with DD (increased E/e’) had significant cardiac inflammation (elevated MCP-1/CD68/IL-1β/IL-18, augmented recruited pro-inflammatory Mφs infiltration, decreased resident pro-resolving Mφs, and increased VCAM-1/ICAM-1) in ventricles. MφFKO were resistant to HypoMg-induced DD and showed decreased inflammation (decreased MCP-1/CD68/IL-1β/IL-18/VCAM-1) in ventricles vs. MφFKO-control. This supported the assertion that Mφ activation is required for DD development. Inhibition of TRPM7 kinase function with TRPM7 K1646R reduced cardiac recruited pro-inflammatory Mφs and normalized the changes of MCP-1/VCAM-1/ICAM-1/IL-1β/IL-18 in HypoMg-mediated DD. In Raw264.7 Mφs, HypoMg caused increased TRPM7 expression and IL-1β secretion. In RL-14 CMs, HypoMg increased expression of TRPM7/MCP-1/VCAM-1/IL-1 receptor. In HypoMg-induced HFpEF, TRPM7 is necessary for inflammatory Mφ activation and plays a role in CM facilitation of inflammatory Mφ migration to the heart. IL-1 receptor activation of CMs likely mediates the interaction between Mφs and CMs in HFpEF.
Liu et al. (Sun,) studied this question.